The hereditary lymphedemas are developmental disorders of the lymphatic system that lead to disfiguring and often disabling edema (swelling) of the extremities together with various associated abnormalities. Most are autosomal dominant with variable expression and age of onset. The primary target tissue in these conditions is the lymphatic system, a poorly understood component of the vascular system responsible for microcirculation of fluids drained from tissues and the return to the blood vascular system, and for trafficking cells of the immune system. Despite its importance in congenital and acquired disease, including cancer, very little is known about the molecular events involved in development of the lymphatic system. As with many other developmental pathways, genes involved in hereditary lymphedema can provide important insights into the molecular events Involved in lymphangiogenesis. We recently identified the gene responsible for hereditary lymphedema-distichiasis (LD). This disorder is characterized by lymphedema and extra rows of eyelashes arising from the Meibomian glands. Associated abnormalities include tetralogy of Fallot, cleft palate, hydrops fetalis and cystic hygroma. The gene responsible for LD is the FOXC2 forkhead family transcription factor. The overall goals of this project are to determine the role of FOXC2 in hereditary lymphedema and in the development of the mammalian lymphatic system. Preliminary data indicates that Foxc2+/- mice have highly abnormal lymphatic vessels and lymph nodes analogous to those in patient's with LD. Specific aims are: (1) to fully characterize Foxc2 +/- and -/- mice, and transgenic mice overexpressing the gene, for lymphatic abnormalities as a model system for lymphedema-distichiasis and abnormal lymphatic development in mammals; (2) to determine the expression patterns of Foxc2 in the lymphatic system during development to begin to assess the mechanism of Foxc2 insufficiency on lymphatic phenotype and development; (3) to begin to establish the role of Foxc2 in the pathways and hierarchy of genes controlling lymphangiogenesis in mammals; (4) to assess the timing of Foxc2 deficiency in lymphatic and other abnormalities by creating mice in which Foxc2 is conditionally expressed during development. From these studies we will learn the precise defects in the developing mouse lymphatic system caused by Foxc2 deficiency, whether Foxc2 expression in lymphatic or other cell types is correlated with these defects, the timing of Foxc2 insufficiency on phenotype, and will begin to determine the role of Foxc2 in the complex biochemical pathways involved in lymphangiogenesis.